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Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases

Abstract

Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis. Myofibroblasts are scar-forming cells that are ultimately responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in fibrosis. Advances have been made in our understanding of the mechanisms that keep myofibroblasts in an activated state and control myofibroblast functions. However, the mechanisms that help myofibroblasts to persist in fibrotic tissues remain poorly understood. Myofibroblasts evade apoptosis by activating molecular mechanisms in response to pro-survival biomechanical and growth factor signals from the fibrotic microenvironment, which can ultimately lead to the acquisition of a senescent phenotype. Growing evidence suggests that myofibroblasts and senescent myofibroblasts, rather than being resistant to apoptosis, are actually primed for apoptosis owing to concomitant activation of cell death signalling pathways; these cells are poised to apoptose when survival pathways are inhibited. This knowledge of apoptotic priming has paved the way for new therapies that trigger apoptosis in myofibroblasts by blocking pro-survival mechanisms, target senescent myofibroblast for apoptosis or promote the reprogramming of myofibroblasts into scar-resolving cells. These novel strategies are not only poised to prevent progressive tissue scarring, but also have the potential to reverse established fibrosis and to regenerate chronically injured tissues.

Key points

  • Organ fibrosis is a lethal outcome of autoimmune rheumatic diseases such as systemic sclerosis (SSc).

  • Myofibroblasts are scar-forming cells that are responsible for the excessive synthesis, deposition and remodelling of extracellular matrix proteins in SSc.

  • Persistent myofibroblast activity leads to progressive tissue fibrosis and distortion of the normal tissue architecture, resulting in organ failure and, ultimately, in death.

  • The termination of myofibroblast activity is suppressed in fibrotic disease by biomechanical and biochemical cues, which assist myofibroblast escape from apoptosis, thereby halting their elimination.

  • Evasion of apoptosis results in persistent myofibroblast activation and/or the differentiation of myofibroblasts into a pro-fibrotic or pro-inflammatory senescent phenotype, thereby preventing fibrosis resolution.

  • Targeting myofibroblast apoptosis and reprogramming these cells to become scar-resolving cells are emerging as novel therapeutic strategies to reverse established fibrosis.

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Fig. 1: Origin, functions and fate of myofibroblasts during tissue repair and fibrosis.
Fig. 2: Intrinsic and extrinsic apoptosis pathways.
Fig. 3: Mitochondrial priming of myofibroblasts.
Fig. 4: Molecular control of myofibroblast activation and survival.

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Acknowledgements

The research of B.H. is supported by the Canadian Institutes of Health Research (Foundation Grant 375597). D.L. gratefully acknowledges funding support from the NIH (grant R01 HL147059–01), the Start-up Package from Massachusetts General Hospital, the Scleroderma Foundation New Investigator Grant, the Scleroderma Research Foundation Investigator-Initiated Research Grant, the American Thoracic Society Foundation/Pulmonary Fibrosis Foundation Research Grant and Sponsored Research Grants from Boehringer Ingelheim, Indalo Therapeutics and Unity Biotechnology.

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The authors contributed equally to all aspects of this article.

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Correspondence to David Lagares.

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D.L. declares that he has received research funding from Boehringer Ingelheim, Indalo Therapeutics and Unity Biotechnology. D.L. also has a financial interest in Mediar Therpeutics, which is developing treatments for organ fibrosis. D.L.’s interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their conflict of interest policies. B.H. declares no competing interests.

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Nature Reviews Rheumatology thanks V. Thannickal and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Stress fibres

Contractile bundles composed of actomyosin filaments.

t-Distributed stochastic neighbour embedding

A technique for visualizing high-dimensional datasets, often displayed in the form of clusters.

Membrane blebbing

Protrusions of the cell membrane that occur during apoptosis.

Pyknosis

Condensation of the nuclear chromatin during apoptosis.

Apoptosome

A multi-protein complex that mediates the initiation of apoptosis.

Granulation tissue

New connective tissue that forms during wound healing.

Molecular rheostat

A system that maintains and controls critical biological processes such as cell death and survival.

CArG boxes

Repeating [CC(A/T)6GG] DNA sequences present within gene promoters.

Secretome

The collection of molecules secreted by cells into the extracellular space.

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Hinz, B., Lagares, D. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nat Rev Rheumatol 16, 11–31 (2020). https://doi.org/10.1038/s41584-019-0324-5

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